IF THERE IS A SINGLE ICON ABOVE ALL OTHERS THAT ART ACQUIRED from science in the twentieth century, it is DNA. And with good reason: this molecule, as Francis Crick famously shouted to the bemused customers of the Eagle pub in March 1953, contains the secret of life. In most representations we see it as a rather stubby double helix, for they seldom show its other striking feature: it is immensely long and thin. In every cell of your body you have two meters of the stuff; if we were to draw a scaled-up picture of it with the DNA as thick as sewing thread, that cell’s worth would be about 200 kilometers long.

Like the fibers of cotton, DNA molecules can stick together side by side to make a visible thread, and this makes possible a rather lovely experiment. So when the contemporary artist Marc Quinn asked me about a DNA exhibit for his show at London’s White Cube gallery in 2000, I was delighted to help. He gave me a sample of his semen (Marc is renowned for using his own body fluids in work that explores the concept of the self; in 1991 he made a cast of his head using eight pints of frozen blood), and I broke open the sperm with detergent and a special chemical that softens their tough

coats. Sperm are basically just packaged DNA, and the solution became very viscous as their contents were released. We transferred a little puddle of it to a tall glass tube, and gently overlaid it with pure alcohol. Then we lowered a glass rod through the alcohol to the puddle, stirred slightly, and slowly drew the rod upwards. Tiny fibers appeared and coalesced into a thread attached to the rod. We pulled it up until it reached the top of the tube, then stuck it to the rim. Marc put the tube in front of a jet black surface, and we stood back and hugged each other at the beauty of it: Marc’s DNA, a web of molecules each too small to see with the naked eye, entwined into a single shining thread. The secret of his life.

You can do a similar experiment with any living tissue—even if you don’t have a laboratory to hand you can get pretty good results in the kitchen using an onion as the source of tissue, and washing-up liquid, salt and vodka to extract the DNA. It will look exactly the same as human DNA, for a very good reason: from a chemical point of view it is exactly the same kind of molecule. DNA is the common thread that links every living thing with a single primeval ancestor.

But your DNA also makes you different from an onion, and from every other human being. The DNA molecule carries a code, and the instructions that dictate whether an egg or a seed grows into a human or an onion are written in that code. Much smaller differences in these coded instructions determine the infinite variety of hair color, facial features, body shape and personality that make each of us a unique individual. Each instruction, or gene, has a small part to play in making the whole, and the overall outcome is determined in part by the environment, but the combined power of the information contained in the whole genome, the entire complement of an organism’s DNA, is truly awesome. The project that is now under way to harness that power through reading and understanding the complete set of instructions that makes a human being—the human genome—is one of the most momentous enterprises in modern

science. It could transform our lives, for better or worse depending on how we apply the knowledge.

Everyone seems to understand this, if the razzmatazz that greeted the June 2000 announcement that the draft human genome was complete was anything to go by. But despite the fanfares, the job isn’t remotely over yet. The reading process will be largely complete some time during 2003, but the understanding will take decades and will encompass all of biology. And the generation that really understands the human genome, or the onion genome for that matter, will understand life.

I never meant to get involved in the three-ring circus of the Human Genome Project. Only ten years ago I would have laughed if anyone had suggested I would soon be directing a research center with a staff of 500, plunging into the politics of an international project and engaging in a war of words in the press. What I wanted to do was to read the genetic code of the nematode worm. I didn’t imagine that the worm was going to lead us directly to the human genome. Certainly, reading worm DNA is a good preparation for reading the DNA of any other species, and that includes humans; but when we started to read the worm genome we had no thoughts of other species. We simply wanted to fill in the background to the ever more elaborate picture of the biology of this tiny creature that had developed over the previous twenty-five years.

I first met the worm in 1969, when I arrived at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge—universally known as the LMB—to work as a staff member in Sydney Brenner’s group. Sydney was joint head, with Francis Crick, of the cell biology division at the laboratory. Physically they were a study in contrasts—Francis was tall and sandy-haired, while Sydney was short and dark with penetrating, deep-set eyes beneath startlingly bushy eyebrows—but both were great talkers. Born and educated in South Africa, Sydney had come to Oxford as a graduate

student in 1952, with a medical degree but determined to work on the biology of the gene. He had quickly established himself among the international group of scientists working on the genetics of bacteriophage—tiny viruses that infect bacteria—who together were laying the foundations of modern molecular biology.

In 1953 Francis Crick and Jim Watson had discovered the double helix structure of DNA, and Sydney had been one of the first to visit Cambridge and hear about the discovery at first hand. He had moved to Cambridge permanently in 1957 and had worked with Francis on deciphering the genetic code and understanding how cells translate it into the protein molecules they need to carry out their functions. By the mid-1960s Sydney considered the work of understanding how genes make proteins almost done, and wanted to move on to the next stage. His ambitious plan was nothing less than to understand how a complete animal was encoded by its DNA. Naturally he wanted to start with something simple, and the animal he chose was the nematode worm. ‘We propose to identify every cell in the worm and trace lineages,’ wrote Sydney in his bid for support for the project. ‘We shall also investigate the constancy of development and study its genetic control by looking for mutants.’ Sydney later recalled that some people thought the idea was crazy. ‘Jim Watson said at the time that he wouldn’t give me a penny to do it,’ he said. ‘He said I was twenty years ahead of my time.’

Why did Sydney pick a worm? There is a long tradition in biology of studying simple organisms in order to discover mechanisms that are at work in all living creatures. At the time Sydney embarked on his project, most geneticists worked with bacteria or the fruit fly Drosophila melanogaster. But neither of these suited Sydney’s purpose. Bacteria are single-celled organisms; one of the main objects of his program was to look at how the genes control the successive cell divisions that turn an egg into an adult in a multi-cellular animal. The fly, on the other hand, with its compound eyes,

wings, jointed legs and elaborate behavior patterns, was too complicated to be susceptible to the sort of exhaustive analysis Sydney had in mind. Nematode worms, or roundworms, were not as well studied as either, but they were far from unknown to biology. They constitute a large family that includes both parasitic and free-living varieties. The species that interested Sydney was a free-living soil-dweller, Caenorhabditis elegans: a long name for a tiny creature only a millimeter from nose to tail.

In the wild, C. elegans lives in soil and feeds voraciously on any bacteria or other micro-organisms it can find. It grows from egg to adult in three days (one-third of the time for a fruit fly), except when food is scarce, when it can hang about in a non-breeding larval form for several months. Most adults are hermaphrodites and produce several hundred offspring through self-fertilization. Males arise occasionally, perhaps at a rate of one in a few hundred, and mating provides the possibility for genetic mixing which allows for more rapid evolution. The worm’s anatomy is quite simple, but although it lacks many of the physiological features of higher animals, such as a heart, lungs and bones, it can still carry out many basic tasks: moving, feeding, reproducing, sensing its environment and so on. It consists basically of two tubes, one inside the other. The outer tube includes the skin, muscles, excretory systems and most of the nervous system; the inner tube is the gut. It moves by contracting its dorsal and ventral muscles alternately, arching its body into a series of S-shaped curves.

The worm is, moreover, well suited to the kind of investigation Sydney had in mind. It is easy to keep and breed in the laboratory, living happily in petri dishes that have been sown with lawns of Escherichia coli bacteria. You can even keep them in suspended animation in the freezer for years at a time, allowing you to preserve stocks of different strains of the animal. Both larvae and adults are transparent, so that, given a good enough microscope, you can see not only the internal organs of living animals but even individual

cells. The adult hermaphrodite usually has exactly 959 cells, not counting the egg and sperm cells. (For comparison, a fruit fly has more cells than this in just one of its eyes, and the human body has 100 trillion.) Its genome is made up of 100 million bases divided into six segments, or chromosomes.

Sydney hoped that he would be able to establish direct links between the worm’s genes and its development from egg to adult, following the classic route of geneticists, in use since the first decades of the twentieth century. With a fast-breeding species, such as a worm or a fruit fly, occasional changes arise in the DNA that make the animal look or behave abnormally. These changes are known as mutations, and the altered animals as mutants. Geneticists soon developed a variety of techniques to increase the normal mutation rate. In the 1960s there was no way to analyze the DNA directly, but by cross-breeding mutants and looking at the patterns of inheritance in later generations you could map the relative positions of the mutated genes on the chromosomes. The closer together two mutations lay on a chromosome, the more likely they were to be inherited together. As well as mapping the genes, Sydney hoped, through careful microscopy and biochemistry, to discover exactly what was going wrong in mutant worms at the level of cells.

Assisted by a succession of young researchers, most of them American, Sydney was initially very successful in finding mutants and mapping the affected genes along the chromosomes, confounding those skeptics who had said that the worm was so boring in appearance and behavior that he would never be able to distinguish the mutants from the rest. But the timescale of the whole enterprise turned out to be longer than Sydney anticipated. Genes almost always work in concert, rather than solo—only very rarely is it possible to follow a direct line through from one gene to one function. Even so, the whole thing took off in a larger way than Sydney could have predicted because his intuition led him to an animal with tremendous potential for research.

As was typical of Sydney’s style—indeed, the style of the LMB as a whole—on my arrival I was given about a meter of space at the bench in a crowded lab and more or less left to get on with it. Sydney and Francis believed that keeping the lab tightly packed encouraged people to interact, and that ‘desks encouraged time-wasting activities.’ I found myself among a group of young researchers, astonished that we were being paid to do what we wanted to do anyway, and knowing that we had no-one to blame but ourselves if we did not succeed. I compared notes with another new arrival, amazed like myself by the pride, to the point of arrogance, that we found at the lab. ‘Who do these people think they are?’, I remember him saying. But gradually we realized that they had a right to be proud, and as time went on we acquired some of that pride ourselves, though personally I was convinced that I could never do well enough to live up to the past glories of the LMB.

The laboratory was then and still is one of the world’s top centers for research into the molecular basis of life. This was the place, more than any other, where the field of molecular biology had been invented. Its unique ethos undoubtedly played a role in shaping my development as a scientist. It grew out of a fortunate combination of circumstances in the years after the Second World War. Many academic scientists had engaged in war-related research, and the results were spectacular: radar, high-speed computing, antibiotics, and nuclear technology all had their origins in wartime research. It dawned on the government of the day that investment in science could have a long-term payoff. Up to the end of the 1930s there was little opportunity to do research in Britain if you didn’t have a university teaching appointment or a private income. But ten years later it suddenly became easier to get grants, generous ones, from government-funded bodies such as the Medical Research Council (MRC) or the Department for Scientific and Industrial Research. This sudden largesse coincided with one of the most exciting periods

in the history of biology, as more and more people began to apply the methods of physics and chemistry to biological problems.

Lawrence Bragg was a physicist who headed the Cavendish Laboratory, the physics department of Cambridge University. As a young man, Bragg had pioneered the technique of X-ray crystallography that made it possible to study the three-dimensional arrangement of atoms in molecules, including biological molecules. Among his staff was a meticulous, quietly spoken Viennese émigré chemist called Max Perutz. Perutz, together with a young colleague, John Kendrew, also a chemist, was trying to decipher the structure of the blood protein hemoglobin. X-ray crystallography worked well for small molecules, but proteins contained thousands of atoms and progress was slow. Bragg, an extremely influential figure in British science, was an enthusiastic supporter of Perutz’s work. In May 1947 he wrote to the Secretary of the MRC asking for the funds to establish Perutz’s group ‘on a more permanent basis.’ Within months the MRC agreed to support a Unit for Research on the Molecular Structure of Biological Systems, with Perutz at its head.

The unit, later given the slightly snappier title of the Molecular Biology Research Unit, was basically Perutz and Kendrew. They were soon joined by two research students, Francis Crick and Hugh Huxley, both physicists returning to academic life after several years of war service. Two years later the arrival of Jim Watson, then a 22-year-old American whiz-kid geneticist, opened up a whole new field of possibilities. Perutz says that it was Watson who made them realize that physics and chemistry might not hold all the answers.

Francis took little persuading that it was more important to work

on DNA, then just beginning to be recognized as the stuff of which genes are made, than on protein. Francis and Jim did little experimental work themselves, but they read, talked, argued and built models, and with the crucial help of an X-ray photograph of DNA taken by Rosalind Franklin at King’s College in London (shown to Watson by her colleague Maurice Wilkins) they correctly inferred the double-helix structure of the molecule and published it in Nature in 1953. I was an eleven-year-old schoolboy at the time, but I remember those years as a time of huge excitement that so much was being discovered.

DNA is a long, thin molecule made up of a chain of units called nucleotides; each nucleotide carries one of the four bases adenine (A), guanine (G), cytosine (C) or thymine (T). Watson and Crick deduced that two strands of DNA wind into a double helix in which A always pairs with T and C with G. They realized that this base pairing provides the mechanism by which DNA can replicate, the fundamental requirement for the evolution of life on earth. Adopting a deliberately insouciant turn of phrase that has passed into scientific folklore, Watson and Crick ended their 1,200-word paper with the sentence: ‘It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.’ In other words, if you have a single strand of DNA and an unlimited supply of the four nucleotides, you can make the second strand, and from this another copy of the first strand, and so on.

A month after their first Nature paper came out, Watson and Crick followed up with another which spelt out a further momentous consequence of their discovery: ‘[I]n a long molecule many different permutations are possible, and it therefore seems likely that the precise sequence of the bases is the code which carries the genetical information.’ They were right; and the practice of biological research has been changed for ever by this understanding. This is the truly remarkable outcome of knowing the structure of

DNA—not the helical form itself, but the confirmation that the system for conveying the instructions for making a life from one generation to the next is digital, not analogue—like the English language, and not at all like, for example, a blueprint. To convey the notion of a furry animal that has whiskers and purrs, a speaker of English says the three-letter word cat, which stands for a cat to all those who understand the language. A blueprint, on the other hand, shows a graphical representation of a cat. Cat DNA spells out genes (the instructions to make a cat) just as the alphabet spells out words in a language. There is no graphical representation—nothing like the tiny homunculus curled up in the head of a sperm which some of the earlier microscopists imagined they could see.

The human genome consists of 3 billion base pairs of DNA, parcelled out into 24 chromosomes. They are numbered from 1 to 22, plus the X and Y sex chromosomes. The nucleus of every cell in our bodies (other than the egg and sperm cells, and red blood cells) contains two sets of chromosomes, one inherited from each parent: two each of chromosomes 1 to 22, plus one X and Y in males, or two Xs in females. If you scaled up the thickness of the DNA chain to that of ordinary sewing thread, you would need a 4 kilometer reel to represent the length in an average human chromosome.

When people talk about the sequence of the human genome, they mean the order of the bases on one of the paired DNA strands from each of the twenty-four different chromosomes. It doesn’t matter which strand you choose, because the sequence of one immediately gives you the sequence of the other, according to the base pairing rule. The details of the chemistry of DNA give each strand a direction (like a series of arrowheads), and, as Francis and Jim recognized, the strands run in opposite directions. Scattered along the genome, some on one strand and some on the other, are stretches of sequence, at first sight no different from the much longer intervening stretches, that are the genes. I’ll go into the way genes work in more detail later on p. 39. For the most part, they instruct the cell to make proteins, which

themselves consist of chains of small molecules called amino acids.

Around the same time that Jim and Francis were solving the DNA structure, a Cambridge biochemist called Fred Sanger was the first to work out the complete sequence of amino acids in a protein, insulin. Fred is a quiet, unassuming, self-contained scientist with a tremendous capacity for seeing a difficult practical problem through to its conclusion. His work on insulin proved beyond doubt that proteins were not assembled according to any simple chemical rule, and that their construction must therefore be directed by a set of instructions encoded in the genes. At that stage Fred worked in the Department of Biochemistry at Cambridge University, not Max Perutz’s unit, but he too was funded by the MRC as a member of its external staff. By the end of the 1950s Perutz and Kendrew had done the seemingly impossible and discerned the three-dimensional structures, formed from elaborately folded protein chains, of both hemoglobin and its smaller cousin myoglobin—the first protein structures to be solved.

It was obvious to the MRC that in supporting molecular biology they had backed a winner. More and more people wanted to join Perutz’s group, which was clearly getting too big to remain in the Cavendish Laboratory. In 1962 the Research Council opened a new, six-story building next to Addenbrooke’s Hospital on the south side of Cambridge. It was called the MRC Laboratory of Molecular Biology (LMB), and Perutz was its first director. John Kendrew, Francis Crick and Sydney Brenner were all still there. Fred Sanger moved across from biochemistry to head the protein chemistry division. There was a constant floating population of short-term researchers and distinguished visiting scientists from all over the world. And the discoveries continued to flow; among them, most importantly for our story, Fred Sanger’s 1975 invention of a method for reading the sequence of DNA. Altogether, nine Nobel prizewinners have made the trip to Stockholm as a result of work they did in the LMB or the unit that preceded it.

The significant point is that the MRC was prepared to finance long-term work. It took Max Perutz twenty-three years (less the war years, when he was first interned as an alien and then released to conduct war-related research) to solve the structure of hemoglobin, and many chemists and biologists thought he was wasting his time. It wasn’t certain, when he began, that proteins even had a stable structure. But Lawrence Bragg supported him, because although he thought Perutz’s project might not work, he knew that if it did work it would be very important. And that was the tradition that pervaded the LMB. It wasn’t regarded as foolhardy to take on projects when you couldn’t necessarily see how you were going to carry them out, as long as they were important enough. You didn’t—and still don’t—have to justify everything in advance; you were just given the time, and a limited amount of space and resources, to get on with it.

Just as important in characterizing the ethos of the LMB in its heyday is that the work was not done in pursuit of any ulterior motive, financial or otherwise. Yes, the discovery of the structure of DNA opened the way to the biotechnology era; but that’s not why Jim and Francis did it. Francis himself put it best in a letter of reproof he dispatched to Jim in 1967 after reading a draft of Jim’s superb account of the discovery, The Double Helix, in which Jim implied that his eyes were always on the Nobel Prize: ‘The major motivation was to understand.’

It was an environment that suited me perfectly. I don’t think I would have survived a conventional academic career, juggling teaching, research and administration in a university. I was incredibly lucky to end up where I did, as my progress as a scientist up to this point had been somewhat erratic. I was without any focused ambition, simply moving from one thing to another as friends and colleagues advised.

Studying science at school and university was no more than a natural progression from my childhood interests. Right from the

beginning I had surrounded myself with construction sets such as Meccano and all kinds of electrical gadgets—I was fascinated by electricity. I made radio sets, and begged a broken-down TV from a TV shop, which I fixed so that you could just about watch it in a darkened room. I kept pond life in an aquarium, and watched Hydra doing its crazy handstands through an old microscope my uncle had given me. Long before I started school biology in any serious way I dissected a dead bird that I had found, and was fascinated to discover that living things were also mechanisms.

My father, an ordained minister in the Church of England, was also interested in things to do with the natural world. My mother, an English teacher, was a very pragmatic person who was happy to answer my and my sister Madeleine’s questions—we would talk and talk. We were not especially well off, although my father had a slightly better income than he would have had as a vicar: he became overseas secretary of a missionary society, the Society for the Propagation of the Gospel. He was never a missionary himself; he joined the Society after having been an army chaplain in Egypt and spent the rest of his career as an administrator.

For me, adolescence meant dealing not just with sexual traumas but with the question of what to do about Christianity. I’d been brought up in the Church and was a complete believer as a young child. But in my teenage years I began to question. My science was beginning to go beyond the realm of fiddling with construction sets; I remember being excited to discover that the mind could reach out and understand things that were very large and very small, from planetary motion to the power in a grasshopper’s legs. I think many scientists have felt that: a sudden overwhelming sense of the power of the human mind. It forces you to look at beliefs based on articles of faith and say, ‘These don’t really measure up; sorry.’ Of course, it’s not that the power of observation and deduction actually disproved the existence of God—there are plenty of scientists who are also believers—it was just that, as a strategy for living, religion didn’t

make much sense to me.

I also differed from my father in my view of human society. He had a conventional view of hierarchy and class, and this was something I was amazed by because for me the central thing about humanity is that we have to be treated equally. But although I couldn’t share his views on religious belief and social class, my father’s influence has always been an important factor in my own approach to life: I grew up with his indifference to material wealth, and his overriding sense that one should work for the common good. Trying to live up to his standards in this respect has been a factor in shaping my views on how we gather scientific information and make it available to others.

I had what amounted pretty much to the usual education for a middle-class boy of the 1950s. I was sent to a local private preparatory school, from where I got a scholarship to the London Merchant Taylors’ School. Originally a sixteenth-century foundation, the school then occupied a range of rather grand, purpose-built 1930s brick buildings surrounded by playing fields, near where we lived in the London suburb of Rickmansworth. It offered a fairly traditional curriculum to academically able boys; I fell naturally into the science stream and went along with the general assumption that I would in due course go to Cambridge and read for a degree in natural sciences.

When I came to Cambridge as an undergraduate in 1960 I was still interested in living things. I wanted to specialize in neurophysiology (living things and electricity, all in one package!). But somehow, either because of my exaggerated expectations or because of the teaching, it didn’t work out, and I ended up with organic chemistry, which was very well taught. I rationalized to myself that organic chemistry was a good basis for biology—I think rightly: it gives you a sense of molecules and what they do, and indeed it’s reasonable to view biology as just a branch of chemistry.

It has to be said that I was not a model student. I started doing

theatre lighting for the Amateur Dramatic Club early on, despite the disapproval of my college dean, who said anyone who got involved in theatre would fail their exams. I duly did rather poorly in my second-year exams. In the Cambridge system this doesn’t matter too much, but it made me realize that if I didn’t get my act together I might fail my finals as well. So I offended my friends in the theatre by backing out of the main production in my final year. I knew I just had to put my nose down and get on with the work. Determined not to fail, I set myself a rigid revision schedule and just kept up with it until the final exams. But it was a total grind: I wasn’t deeply interested. I managed to get a 2:1—an upper second-class degree—but it was a bit of a near squeak.

I never meant to do a Ph.D.. It was quite clear that I had no talent or taste for this book-learning stuff, so I signed up to go abroad with Voluntary Service Overseas. Then, as it happened, my VSO scheme fell through just as I got my results. I wandered along to the chemistry labs, more or less on the rebound, and asked about becoming a research student. It was the 1960s, a time of university expansion: the doors were open, and a 2:1 was good enough to get me in. I couldn’t have done it now.

I joined a group under Colin Reese, a young lecturer only four years into his first teaching job, who was working on nucleotides, the building blocks of DNA and RNA. RNA is another nucleic acid that carries the coded DNA instructions out of the nucleus and acts as a template for the assembly of proteins. Colin was interested in using chemical methods to make synthetic nucleic acids by stringing nucleotides together in a predetermined order. A lot of advances in biology, including genome sequencing, have depended on the availability of synthetic DNA and to a lesser extent RNA. But Colin worked on the problem mainly because he found it scientifically interesting. I went into this with no thoughts of solving great problems in chemistry, but after a few weeks I was completely obsessed. It was like being back in my bedroom at home with all the

toys. Every day there was a practical problem to solve, and it was fun finding ways to make things work. I did what I liked, and often did it differently from the way you were supposed to, and then of course you stumble across things. I learned about everything: mass spectrometry, nuclear magnetic resonance—all the new big toys I managed to wangle my way into as research students do. I synthesized new compounds and got my name on lots of papers. Colin wrote it all up—I had nothing to do with it, I was a technician—but I had a lot of fun, learned some chemistry and got a Ph.D. at the end of it.

The question of what I should do next was solved for me more or less before I even began to think about it. Colin knew Leslie Orgel, a former Cambridge chemist who had recently moved to the Salk Institute in La Jolla, California. Leslie had started out as a theoretical chemist in Oxford, but after moving to Cambridge and hanging out with the molecular biologists in Perutz’s unit, he went off in a completely new direction. He was now doing practical organic chemistry in an attempt to work on the mechanisms by which life might have begun on the primitive earth. At the Salk he was building up his group and asked Colin to recommend people, and Colin gave him my name. I guess Leslie knew that Colin’s students were well trained and were likely to get something done. I was the second of them to be invited, joining a trail of young Ph.D.s going over there and having a good time in Leslie’s lab, being spoiled and taken out to dinner with the great and good of science.

The year 1966 was extraordinary. As well as finishing my Ph.D. and getting a job in California, I had got married. During my second year as a research student I had met Daphne Bate, a research assistant in the geophysics department who used to come round with a friend for dinner regularly at the flat I shared with one of their colleagues. During that year Daphne and I didn’t pay any particular attention to each other, but a bit later we began to realize that we wanted to be together. Within a few months we had to face the

question of what was going to happen next. Was Daphne to give up her job to go with me to California? And if so, should we get married? It was quite clear that both sets of parents would be very upset if we went to America together unmarried. So eventually, after much discussion, we married in the late summer, not long before I was due to leave.

Just as we arrived in California we realized that Daphne was pregnant, which was completely improper and not planned. We thought we were going to be destitute; we knew that health care in the United States was expensive, and although general health insurance came with the job it did not cover pregnancy and childbirth. But somehow everything worked out fine. My post-doc’s salary was enough for our simple tastes. Instead of living in an apartment near the La Jolla campus like the other post-docs, we rented a wooden house in an unfashionable area near the beach at Del Mar. We grew vegetables in the garden behind the house, and we saved enough money for paying the doctor’s bills not to be a problem. We continued to live very happily in that house after our baby daughter Ingrid was born. We’d bought an old pickup and we used to drive to the beach with the pram in the back. Sometimes I’d walk the five miles along the coast to the lab. It was completely unspoiled and very beautiful. On our holidays we visited national parks from Canada to Yucatan in an old VW Beetle we’d bought when we realized that the pickup wasn’t up to long journeys.

I sometimes describe myself as a child of the sixties, and that’s all the excuse some journalists have needed to label me an ‘ex-hippy.’ But my experience of the sixties wasn’t like that at all—it was nothing to do with rock concerts and dropping out. It was a matter of not living lavishly but enjoying what you had, growing things with your hands, working hard but not being tied to a nine-to-five job, and generally feeling that there’s more to life than money. And all this was set against a background (in the U.K.) of sufficient spending on public services, which gave a great sense of security. I

regret that nowadays we seem to have lost too much of that, and live in a world in which we are materially richer but apparently nothing matters except next year’s bottom line.

I stayed in Leslie Orgel’s lab for two and a half years. It was very different and exciting, and broadened my scientific horizons enormously. It was there that I first really understood the concept of evolution—partly, as so often happens, because I had to explain it to someone else. How is it that the chance events of environmental and genetic change can give rise to organisms that seem perfectly designed for their lifestyles? How, indeed, did life evolve from non-living matter in the first place? The sole requirements for evolution are replication and inherited variation. In other words, the evolving organism must be able to reproduce itself, must do so imperfectly, and the variations must be transmitted to the next generation. A crystal replicates itself when placed in a saturated solution of its salt, but it cannot evolve because there is no inheritance of variation.

The beginnings of evolution and the origins of life are one and the same. Once something is replicating with variation, it will bit by bit explore the possibilities of its environment. Its more successful descendants will colonize at the expense of the less successful: the process described by Charles Darwin which he called natural selection. Leslie put me on his long-standing project to investigate how the first nucleic acids might have replicated without the evolutionary more recent enzymes that are essential to the process in all modern organisms. I didn’t make a big contribution, but we obtained some results that we wrote up. Since then the lab has worked to look for analogues to nucleic acids that might have formed on the primitive earth, to see whether they could replicate more easily.

For me, the time eventually came to move on once more. There were two options open to me. There was a move to establish a middle tier of staff at the Salk, between the founding fellows and the post-docs, and Leslie proposed to put me up for one of these

positions. At the same time I heard from Francis Crick, who was then a visiting fellow at the Salk, that he and Sydney Brenner were expanding the cell biology division at the LMB back in Cambridge and were looking for staff. I remember Francis coming to interview me. It probably wasn’t the first time we’d met, because Francis made regular visits to the lab. We sat on lab stools at my bench, and I chatted to him about what I was doing. I didn’t treat it as a formal job interview, and as far as I could tell, neither did he. But I found out later that he’d also written to Colin Reese to ask him for a reference, and the upshot was that Sydney invited me to come and join the group.

Daphne and I were faced with a difficult choice. We loved the open spaces of America, and intellectually the Salk was an exciting place to be. But accepting a permanent post there would be a big step. Daphne wanted to go back to England, and although I was more neutral my parents and sister were there and I had a certain sense of rootedness. If I had been more ambitious I would probably have stuck with Leslie, but at the time other things seemed more important, and in any case I wasn’t really ready for the sort of independent position that he had in mind. We decided to accept Sydney’s invitation, going to the LMB on a one-year visit, but keeping open the option of returning to the Salk afterwards. In the summer of 1969 we took a last trip, driving right across to Florida, back up to Chicago and over the border into Canada, before ending up in New York where we sold the old VW. This was America, freedom and openness! Then Daphne, Ingrid and I flew back to England.

For the first few weeks we felt quite lost. I remember being astonished at how small everything looked—the cars, the houses. But we soon got our bearings, bought a car and found a house—we’d come home with almost enough saved for the deposit—in Stapleford, a village a couple of miles south of Cambridge. Daphne was pregnant again (planned this time!) and our son Adrian was

born later the same year. By the time Leslie put us on the spot when he visited a year later and asked me to decide whether to return to the Salk, we had become happily settled as a family in Cambridge, and decided to stay put. We’ve lived in the same village ever since, with just one move of half a mile to the house we live in now. As they grew up, Ingrid and Adrian could cycle to the local village primary and secondary schools, then to sixth form college in Cambridge itself. Daphne enthusiastically began a new career as an academic librarian.

Sydney had been working on his worms for five years when I arrived, with only two other permanent people in the group. Nichol Thomson was an electron microscopist. One of the reasons Sydney had chosen C. elegans for his project was that Nichol had already taken good pictures of it with the electron microscope, shaving worms into fine slices so that you could see the structure of every cell in section. Then there was Muriel Wigby who assisted Sydney with the genetics, breeding mutant strains and tracking the mutant forms through the generations in order to locate the genes. Sydney was primarily interested in the uncoordinated mutants, worms with genetic defects that disrupted the graceful sinuosity of normal worm locomotion, though he collected everything he saw, both as markers for genetic mapping and for general interest. Working with no other help at first, he found many genes that could give rise to this form of defect, and named them unc-1, unc-2, unc-3 and so on. He hoped he would be able to look at the electron micrographs, see the changes in the anatomy of the muscles or nervous system, and correlate those with the genes and with the behavior of the worms to reveal how the whole system of locomotion was controlled. But that was only part of his plan. As Sydney wrote in his original proposal, he wanted to trace lineages. By that he meant following the sequence of cell divisions that would turn a fertilized worm egg into a fully differentiated adult. It had been known for almost a century that every

individual worm was likely to develop through exactly the same sequence of steps, which is not the case in mammals or even in flies. Once he knew how development progressed normally, he could begin to ask questions about how the genes controlled that process. But it was not an easy task, and those charged with undertaking it had made only limited progress.

Like several others in the group, I originally worked on the chemistry of the worm nervous system—identifying those nerve cells, or neurons, that used particular chemical neurotransmitters to communicate with their neighbors. The idea was to find mutants that affected the production of neurotransmitters. I tried out a technique that I’d learned during one of the Salk Institute’s regular summer schools, when scientists from elsewhere in the United States would come to our beautiful clifftop campus by the Pacific and teach practical courses. By then I already knew I might be working on the worm with Sydney, so it seemed a good idea to learn some neurochemistry. I learned to do a reaction that involved gassing freeze-dried tissue sections with formaldehyde. The reaction gives you a beautiful fluorescent derivative of the neurotransmitters adrenaline, noradrenaline and dopamine, so that the cells light up under the microscope. I had little idea what the point of it was, but it was a trick that I could do.

In Sydney’s lab I had a go with it on the worm. To begin with I couldn’t get it to work, because worm neurons are much smaller than the mammalian neurons I’d worked with before: some of the nerve fibers are less than a thousandth of a millimeter across. The problem was to get the changes in temperature right during the freeze-drying process so that the neurotransmitter molecules didn’t diffuse out of their original positions. I found a way of doing this using a combination of a cold block of metal and high vacuum that worked better than much more elaborate devices. I got very beautiful pictures: the detail was quite exquisite. You could see little packets of green vesicles and plot out the patterns of the neurons. I

found that the transmitter in the vesicles was dopamine, and over the next few months collected several mutants that had abnormal patterns. Playing with these mutants led me directly to the discovery of another class of mutants that lack the sense of touch, tested by stroking the worms with a single eyebrow hair. These proved to be a rich source of study for Marty Chalfie, an American post-doc who arrived in the lab later and subsequently set up his own worm lab at Columbia University in New York.

It didn’t seem to matter what you did—the worm was still virgin territory, you just couldn’t help finding things. At some point during the first three years, Sydney put me on to determining the quantity of DNA in the worm’s genome. The technique involved making a comparison between the genome you were interested in and the genome of the bacterium E. coli. It both measures the size of the genome and gives an idea of how much of it is taken up with repetitive sequences that don’t add anything to the information content. The answer I got was that the C. elegans genome was twenty times the size of E. coli’s, which at the time we thought meant 80 million bases (megabases). But when E. coli was accurately mapped, it turned out to be larger than was previously thought, so the worm estimate was revised to 100 megabases. Years later, when we finished sequencing the worm, we found that was spot on. Better than I deserved, really: some of my other measurements at the time weren’t so precise. The measurements also showed that the worm genome included 15 percent of repetitive sequences—something that caused trouble when we started sequencing.

I did a few other experiments with worm DNA, and helped an American Ph.D. student, Gerry Rubin, to do some similar work with yeast. Gerry, originally from Boston, Massachusetts, was ambitious but at the same time pragmatic and cheerful. Although still a student, he was full of confidence, going out and setting up collaborations with other scientists. We were very limited in what we could achieve, because the tools for analyzing DNA in any detail had yet

to be invented. But we did what we could: the important thing was that we were working with whole genomes, the complete set of instructions for each organism. By the time Gerry went back to the United States in 1974, studies of genomes were about to take off. Restriction enzymes and cloning, key tools in modern molecular biology, had just become available. That meant you could chop up a whole genome into fragments and grow clones of the fragments in bacteria; the full set of clones constituted a library of the genome. With such a library at your disposal, you could at last begin to marry up the genetic information derived from studies of mutants and breeding experiments with the physical information carried in the DNA. Gerry immediately began work on a library of the genome of the geneticists’ favorite species, the fruit fly, and later became one of the world leaders in fly molecular genetics.

My own future seemed much less certain. Unlike most of the other young researchers, I was a member of the MRC staff rather than a visitor funded by a grant. But the post was not a permanent one. We had two children and a house, and I really needed some long-term security. I liked what I was doing at the LMB, but could not see how it could justify giving me a tenured position such as those held by much more established scientists who ran their own research groups. I hadn’t even written any papers—the first to come out with my name on it since I arrived was the one with Gerry on yeast DNA, but that was really his work. I talked over the problem with Sydney, and then with Max Perutz, the LMB’s director. Max came up with the idea of a kind of ‘second-class’ tenured position, and asked if I wanted to be taken on on that basis. I accepted with relief; it meant financial security for my family, without the burden of responsibility that I felt would come with being a fully fledged staff member and having to run a group.

At almost the same time I embarked on a new project which at last would both give me something to put my name to and represent a real contribution to the growing picture of worm biology that

Sydney and his colleagues were developing. While I was drawing the patterns of dopamine cells shown up by the formaldehyde staining method, I’d made other pictures using a different stain to show up all the cell nuclei, and was trying to match up the two sets of pictures to work out which nuclei belonged to neurons. I suddenly realized that when worms were first hatched they didn’t have as many neurons in the ventral cord, the main nerve pathway that runs the length of the worm, as when they were older. But all the textbooks said that nematodes had their full complement of cells when they hatched from the egg. And I said, ‘Look, there are fifteen ventral cord neurons when it’s hatched, and fifty-seven when it’s older. How?’ I was intrigued. One of Sydney’s original aims had been to study the lineages of cells in the worm embryo; now it seemed that the cells continued to proliferate in the larva, and the question of how they did it was up for grabs. It was something I immediately wanted to pursue.

The lab had bought a special type of microscope for studies of the embryonic lineage, called a Nomarski or differential interference contrast microscope. Not only did it magnify more than 1,000 times, it also enhanced the contrast between different regions of the specimen, so that you could see individual nuclei of cells in living tissue without having to stain them. But previous researchers had never been able to follow beyond the first few divisions of the fertilized worm egg, and eventually they gave up.

If it was so difficult in the embryo, how was I going to do it in the larvae, which had a tendency to wander off just as you had them in focus? People had previously tried to stop the worms moving by squashing them or anaesthetizing them, but the results were never any good. It turned out that there was a trick to doing it. I made little agar pads, nicely smooth at the top and not very thick, so that I could focus on the worm and illuminate it properly through the agar. I popped a worm larva onto the agar and dropped a cover slip over the worm. I had painted a layer of bacteria—worm food—in

the middle of the cover slip, on the underside. The worm would browse on the bacteria in this field, and every time it got to the edge of the bacteria it would turn and come back in. And it was happy—like a cow in a field. Cows aren’t moving around much because they’re happily munching, and worms are the same. Now, to my amazement, I could watch the cells divide. Those Nomarski images of the worm are the most beautiful things imaginable. And they’re moving—you can see the worm undulating slowly around, munching, and you can watch the nuclei at the same time. I still find it incredible.

Seeing the first cell divisions in the worm larva was an absolute revelation: just knowing it was possible was extraordinary. In one weekend I unravelled most of the postembryonic development of the ventral cord, just by watching. I found out exactly where the extra forty-two cells came from. The first ten moved into the ventral cord from outside the plane of focus; the original fifteen did not themselves divide. But the ten new cells did, each producing six descendants, one of which was not a neuron. Of the fifty new neurons, four migrated to a different region and four died, leaving forty-two, which with the original fifteen made the adult complement of fifty-seven.

I began to draw what I saw, filing my drawings in a series of green ring-binders that still sit on the shelf in my office. I made my own representations of the nuclei. Looking at the books now, you can see that as I went on I got more and more confident. It became a routine: I’d pick up a worm of the correct age and say ‘I’ll follow this.’ Some cells I followed for days: I found that if I put the larvae in the fridge overnight the cells would stop dividing where they were, and carry on the next morning when they warmed up again.

I didn’t know anything at the time about what the ventral cord cells did, other than that they were nerve cells. But I knew someone who did. Working in Sydney’s group was John White, who had joined at the same time as me. Because molecular biology was a

relatively new field, most of the researchers at the LMB had trained in other disciplines, and John was no exception: before coming to the lab he had worked as an instrumentation engineer. Now he was in charge of reconstructing the anatomy of the worm nervous system. Nichol Thomson, slicing up the worm like salami, had produced a complete set of fixed and stained sections which had all been photographed with the electron microscope. Sydney hired John initially to develop a computerized system for tracking and recording the nerve cells through the 20,000 or so electron micrographs. He bought a computer and John got to work designing a device to view the pictures. But he gradually realized that the storage and processing capacities of the computer, even though it was quite an advanced model for its time, were inadequate to the task. And because in many respects the worm was so simple—the ventral cord was just a bundle of parallel fibers, for example—it turned out to be just as efficient to do it by eye.

John is a wonderful scientist, a sophisticated engineer who is always willing to fall back on simple methods if necessary. He abandoned the computer and gave the job to a technician in the division, Eileen Southgate. ‘She would go through the successive sections marking processes she saw as equivalent,’ he says. ‘Then we’d get together and sort out anomalies.’ This worked splendidly, and in time they were able to draw the complete wiring diagram of the worm’s nervous system. Eventually published in 1986, The Mind of the Worm described all 302 nerve cells and the 8,000 connections between them—a magnificent achievement. Meanwhile John invented many devices for worm microscopy, but his big commercial success was the first practical confocal microscope which he and others in the LMB developed in the late 1980s. By shining an illuminating beam on a narrow point, focusing the detector on the same point and scanning to and fro, it enabled you to look at whole samples of tissue, rather than thin sections, focusing at different depths throughout the sample.

Although the computer didn’t serve the worm’s nervous system very well, it did change Sydney’s direction. He disappeared into its electronic bowels and wrote his own operating system. The lab became a dangerous place for those of us who liked to be in around midnight. If caught by Sydney, one would find oneself listening to the latest twists of the cybernetic plot until the small hours. This was very strange to me at the time, but years later I fell prey to the same bug when we started the map of the worm genome, and throughout the mid-1980s I programmed obsessively.

At the time I was working out the ventral cord lineage, John had just about completed his analysis of the ventral cord anatomy. I burst in to see him on the Monday morning after my weekend’s work (he’d been off sailing, so I couldn’t get hold of him any sooner) and showed him my pictures. He was soon able to see that the seven different types of motor neuron (the nerve cells that control the worm’s movement) he’d identified in the ventral cord each had characteristic lineage histories. It was an early example of Sydney’s grand plan coming into effect: working on quite separate projects, John and I had fortuitously arrived at a common understanding of a small part of the worm’s biology. As the work went on, the excitement affected the whole lab. At one point Sydney bet John a bottle of wine that a particular cell would have a particular history, and lost. He handed over the bottle at a group meeting in the seminar room, and, not having a corkscrew to hand, John decided to open it by injecting pressurized freon gas through a hypodermic needle. The resulting fountain of red wine left a stain on the ceiling for many years afterwards, a reminder of the euphoria of that time.

Despite the success of my first study, it wasn’t immediately obvious to me that it was worth doing the whole lineage. But in the autumn of 1974 there was a new arrival in Sydney’s lab. Bob Horvitz originally hailed from Chicago and took degrees in math and economics at the Massachusetts Institute of Technology before going to Harvard to do a Ph.D. in biology. Bespectacled, intense and

extremely thorough in his approach, he arrived at the LMB steeped in the high-tech ambience that he had absorbed as a research student first with Jim Watson and then with another pioneering molecular biologist, Walter Gilbert, who was developing an alternative method of DNA sequencing to Fred Sanger’s. When Bob looked at what I had been doing, just looking down a microscope and drawing, he was unimpressed. ‘Where are the data?’ he asked me. He couldn’t understand how you could do any kind of analysis if you didn’t have something like a tape of readings from a scintillation counter. I asked him, ‘What makes you more ready to believe what your eyes see on a little piece of paper that’s processed the contents of tubes in a machine than what your eyes see when they look directly through a microscope?’ I convinced Bob that they were both data, and that my observations were at least as rich in data as his measurements, if not more so.

It was Bob who eventually said, ‘Look—the rest of the lineage is just waiting to be done, why don’t you do it?’ (It was not to be the last time that Bob tried to get me organized.) But I said, ‘No, it’s too much.’ One way or another, we decided to do the larval lineage together. Just as I had begun with the nervous system, Bob began with muscle cells, which also multiplied in the period between hatching and adulthood. It was the first of a number of successful partnerships I’ve enjoyed in my scientific life. We never formally divided up the lineage between us—we just started with different parts, sometimes we worked together to solve a particular problem, and we kept going until it was complete. The only part we didn’t do was the development of the gonad. I’d written to David Hirsh, one of Sydney’s earliest American visitors, who now had his own lab in Boulder, Colorado, to tell him about the lineaging. I knew that his lab was working on the development of the gonad, so I said, ‘Why don’t you do your bit if you want to?’ He wrote back immediately, saying, ‘Your letter blew my socks off.’ He gave the project to his student Judith Kimble, so she was working on that at the same time

that Bob and I worked on the rest of the worm. We published the post-embryonic lineage in 1977, not long before Bob returned to the United States to set up his own worm lab at MIT. Judith and David published the gonad lineage a couple of years later.

I met Judith for the first time at the first of the international worm meetings, which was held at the Marine Biological Laboratory at Woods Hole in Massachusetts in 1977. These occasions are great opportunities for networking and cementing the relationships that hold a research community together. On the strength of our conversation at Woods Hole, Judith decided to come and do her post-doctoral stint with me. It was the first time I’d had anyone to supervise, but fortunately she neither needed nor wanted very much supervision. Tall and blonde, she struck me immediately as strong and independent-minded—and, just as immediately, she saw that there was no risk that I would try to control what she did.

In the couple of years after we finished the post-embryonic lineage Bob Horvitz, Judith Kimble and I turned from asking what happened in the developing worm to asking why it happened. A big question in studies of development is: What determines the fate of each cell? Is it genetically preprogrammed to become a nerve cell or a muscle cell—or even to die, as we discovered that some specific cells always did in the course of development? Or does it develop its identity in response to signals from its neighbors? Because the worm was so unwavering in its progress from one fertilized egg to 959 adult cells, it provided an ideal opportunity to answer these questions. We tackled them via two methods, laser ablation and genetics. John White invented a device, using a laser, to knock out

just one cell in a worm, either in a developing animal or an adult. It was a technique that appealed to me, being simple and quick. We used it to show that the invariance of worm development was not entirely down to individual cells, but sometimes depended on interactions between certain cells and their neighbors. At the same time, Bob went looking for mutant worms that had the wrong number of adult cells, in the hope of finding genes that influenced normal development. He did the breeding experiments, and I looked at the lineages in the mutant worms. By the end of the 1970s we’d found twenty-four mutants that implicated fourteen genes directly in controlling cell division, and it was clear that different genes affected different lineages. We realized almost at once that the story was going to be much more complicated than one gene controlling one cell division. It would be a matter of several genes acting in concert at each stage—and we’re still right at the beginning of understanding how this works.

I enjoyed the experiments with laser ablation and lineage mutants, but I had a sense of unfinished business. We had documented all the cell divisions in the larva, but what happened before the eggs hatched was still a mystery. Many people thought it was impossible to follow all the divisions in the embryo. The results of the various attempts that had been made were little better than had been achieved at the turn of the century, for other nematodes, by researchers who looked at fixed and stained embryos and tried to put them in order. I could see that the question needed a new approach, but for a long time I hesitated.

In 1977 something came up that should have got me going on it. At the Woods Hole worm meeting I was taken aside and told that a paper was being submitted from one of the other labs describing the embryonic lineage of the gut cells. But there was a dispute; others were doubtful whether the lineage was correct, and it would be better for the worm community if this was sorted out quickly. Would I look for myself and arbitrate? Well, that was an interesting

and flattering challenge. The gut cells are the largest and easiest to follow, and within a couple of sessions I could tell that the proposed lineage was incorrect. A few days later I sent a report containing the complete gut lineage to everyone concerned, and the paper was withdrawn.

But it was only in 1979 that I started looking again, casually at first. Indeed, something that may have helped was a sense of despair. I had now been at the LMB for ten years. With only a handful of papers to my name since my arrival, I had achieved little as far as I could see, and felt it was high time to move on and do something different with my life. I tentatively enquired about a couple of jobs outside research. But my explorations hadn’t turned up anything that I thought I would be any better at, so it was in a black mood that I first sat down again at the microscope.

I started looking at some of the bigger cells on the outside of the embryos, and began to assemble more fragments of the story. Gradually I developed a schedule of planned sessions, working around the embryo. I worked out that if I was to finish the job, it would take a year and a half of looking down a microscope every day, twice a day, for four hours each time. It seemed crazy, and I consulted John White about whether it was worth doing. ‘Am I really going to do this?’ I asked him—and John said, ‘Yes, sure.’ He and Eileen, after all, were spending year after year poring over electron micrographs in order to produce the complete wiring diagram of the worm’s nervous system.

So, to the surprise of some of my colleagues, I shut myself away for a year and a half and devoted myself to the embryonic lineage. Whereas the laser ablation and lineage mutant experiments had been quite social activities—Judith remembers that we talked for up to five hours a day during her first year as a post-doc in 1978–9 —working on the embryonic lineage was an entirely solitary endeavor. I had a little cubby-hole off the main lab to do the microscope work, and I spent almost all my time in there. Most days

would include two sessions of four hours or so watching cell divisions. With the postembryonic lineage you could afford to leave the microscope for ten minutes or so in the course of watching a cell, but not with the embryo—things happened too fast. You had to concentrate totally. One difficulty was making sure that I didn’t become muddled about which cell was which: they all look alike. So I made a classic cross-hair from spider’s gossamer and used it to pinpoint a cell in the area I wanted to watch. Then viewing was much more relaxed.

After a year and a half it was done. Many people wouldn’t have seen the point; many still don’t. In molecular biology, tasks of this kind are called ‘Hershey heaven’, after a remark of Alfred Hershey, one of the key members of the group who laid the foundations for much of modern genetics in the 1940s and 1950s through their studies of tiny viruses called bacteriophage: you come in every day, you do the same experiment, and it always works. It’s rather like doing a huge jigsaw puzzle—it may be difficult, but you finish it off, partly because it’s the best possible excuse for saying, ‘Don’t bother me, I’m busy,’ but also because you think it’s important. And it goes better and better because you’re training yourself to do that particular task exceptionally well. That it’s important is crucial, though: there’s no point in continuing with something that’s turning out to be valueless. With very big projects, if you’re collecting very high-quality data, which you know contains a lot of information even though you can’t get it all out at the time, then it’s worth pursuing to the end.

That was true of the worm lineage, just as it later proved true of the genome sequence. The lineage is now a resource that people refer to all the time. Coupled with the anatomy, it makes it possible to identify the sites where genes act. The lineage, to quote Bob Horvitz, ‘has given single-cell resolution to worm biology.’ And it’s not relevant only to worms. We discovered, for example, that certain cells consistently die during development. Bob Horvitz and his

colleagues went on to unravel the genetic control of this form of cell death, which turns out to have parallels in many other species, including humans. Activating the cell death mechanism could be a route to treating cancers, while suppressing it might help in the treatment of degenerative diseases.

Some time after I’d finished with the embryo, John White invented a recording device, using an optical disk, that really did allow the embryonic lineage to be reconstructed without direct viewing. And others are now trying to develop a fully automatic method using fluorescent markers. Sometimes people say: ‘Aren’t you sorry you wasted your time?’ But of course I didn’t waste my time; you have to make a start somehow, and then eventually the first approach is displaced by better ones.

To be in Sydney’s division at the LMB in the 1970s was to be in at the birth of an international community of worm biologists. The great majority of today’s worm researchers either came to work with Sydney or are scientific descendants of those who did. Bob Horvitz, now at MIT, and Bob Waterston, now at Washington University in St. Louis and my closest collaborator on both the worm and the human genomes, were among the early ones. Judith Kimble left to start her own lab at the University of Wisconsin—Madison. John White stayed at the LMB until 1993; now he, like Judith, has a lab in Madison. Donna Albertson came as a visitor, married John, and stayed on. Jonathan Hodgkin was the third of the three Jo(h)ns, and we four were more or less permanent fixtures in the lab while others came and went. One of Sydney’s first Ph.D. students, Jonathan stayed at the LMB until very recently, when he moved to Oxford as professor of genetics. There are dozens of others, and the worm community as a whole now has thousands of members. But it retains the extraordinary community spirit that developed at the LMB.

Sydney’s personal influence was undoubtedly hugely important,

but the nature of it is hard to pin down. His notion of supervision was to throw out the odd idea and then go away and leave you to it. There would be no weekly lab sessions to check on progress; but he might turn up and quiz you at odd hours. He would talk about nothing in particular for hours in the coffee room or the corridor, but if you needed to talk seriously to him he would suddenly become elusive. I have vivid memories of trying to have conversations with him through a pair of closing lift doors as he left at the end of the day. He was never in a hurry to publish—it was five years after my arrival at the LMB that we finally published our first paper together, on worm DNA. He is not someone who suffers fools gladly, and he was a master of the cutting put-down. I treasure the reply he gave when I told him my anxieties about the tenure issue, saying, ‘I don’t want to carry the can for all of this.’ Said he: ‘Don’t worry, I’ll carry your little can for you.’ His is a complex and powerful personality, and he dealt ruthlessly with anyone he saw as a potential competitor. But he single-handedly started C. elegans research, and we all learned a lot from him.

People congregated in the coffee room at certain times of day. After lunch, Sydney would hold court, talking for an hour on any topic with the young researchers gathered at his feet. Coffee-time in the morning or tea-time in the afternoon were opportunities to talk about science with anyone who was passing through. After the first year or two I tended not to go to these gatherings so often, but Friday evening at the hospital bar, the Frank Lee, became a regular drinking session. One evening in the summer we used to go punting up the river and have supper at the Green Man at Grantchester. We’d come back down well tanked up, flopping in and out of the river, letting the punts float down more or less on their own, with candles on the front. The Cambridge worm group does much the same to this day. Another fixture was the Guy Fawkes night celebrations, with a bonfire and fireworks, held round at our house every year for years and years. Lots of worm people remember those evenings with

tremendous pleasure. I’ve no doubt it’s one of the activities that built a community. No one thing was essential, but people used to talk until quite recently about coming back to visit ‘Mecca’—the worm group at LMB.